prsandoz entecavir - sandoz canada

Sandoz Entecavir of 40

PRODUCT MONOGRAPH

PrSandoz Entecavir

Entecavir Tablets

0.5 mg

Antiviral

Sandoz Canada Inc.

110 Rue de Lauzon

Boucherville, QC

J4B 1E6

Date of Preparation:

October 24, 2018

Submission Control No: 220844


Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION ........................................................ 3 SUMMARY PRODUCT INFORMATION........................................................................ 3 INDICATIONS AND CLINICAL USE ............................................................................. 3 CONTRAINDICATIONS ................................................................................................... 3 WARNINGS AND PRECAUTIONS ................................................................................. 4

ADVERSE REACTIONS ................................................................................................... 6 DRUG INTERACTIONS ................................................................................................... 9 DOSAGE AND ADMINISTRATION ............................................................................. 10 OVERDOSAGE ................................................................................................................ 11

ACTION AND CLINICAL PHARMACOLOGY ............................................................ 11 STORAGE AND STABILITY ......................................................................................... 18

DOSAGE FORMS, COMPOSITION AND PACKAGING............................................. 18

PART II: SCIENTIFIC INFORMATION .............................................................................. 19 PHARMACEUTICAL INFORMATION ......................................................................... 19

CLINICAL TRIALS ......................................................................................................... 20 DETAILED PHARMACOLOGY .................................................................................... 26

TOXICOLOGY ................................................................................................................. 27 REFERENCES .................................................................................................................. 36

PART III: CONSUMER INFORMATION ............................................................................. 38


PrSandoz Entecavir

Entecavir Tablets

0.5 mg

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of

Administration

Dosage Form /

Strength

Clinically Relevant Nonmedicinal

Ingredients

Oral Tablets, film-coated,

0.5 mg

Lactose Monohydrate.

For a complete listing see Dosage Forms,

Composition and Packaging section.

INDICATIONS AND CLINICAL USE

Sandoz Entecavir (entecavir) is indicated for the treatment of chronic hepatitis B virus infection

in adults with evidence of active viral replication and either evidence of persistent elevations in

serum aminotransferases (ALT or AST) or histologically active disease.

This indication is based on efficacy and safety data in nucleoside-treatment-naive and in

lamivudine-refractory adult patients with HBeAg-positive or HBeAg-negative chronic HBV

infection with compensated liver disease and on more limited data in adult patients with

HIV/HBV co-infection who have received prior lamivudine therapy.

CONTRAINDICATIONS

Entecavir is contraindicated in patients with previously demonstrated hypersensitivity to

entecavir or any component of the product. (For a complete listing, see Dosage Forms,

Composition and Packaging section).

WARNINGS AND PRECAUTIONS

Severe acute exacerbations of hepatitis B have been reported in patients who have

discontinued anti-hepatitis B therapy, including entecavir. Hepatic function should be

monitored closely with both clinical and laboratory follow-up for at least several months in

patients who discontinue anti-hepatitis B therapy. If appropriate, re-initiation of

antihepatitis B therapy may be warranted (see ADVERSE REACTIONS: Exacerbations of


Hepatitis After Discontinuation of Treatment).

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been

reported with the use of nucleoside analogues, including entecavir, alone or in

combination with antiretrovirals. Patients with decompensated liver disease may be

at higher risk for lactic acidosis.

Limited clinical experience suggests there is a potential for the development of resistance to

HIV (human immunodeficiency virus) nucleoside reverse transcriptase inhibitors if

entecavir is used to treat chronic hepatitis B virus infection in patients with HIV infection

that is not being treated. Therapy with entecavir is not recommended for HIV/HBV co-

infected patients who are not also receiving highly active antiretroviral therapy (HAART).

(see WARNINGS AND PRECAUTIONS: Patients co-infected with HIV and HBV)

General Sandoz Entecavir tablets contain lactose and are not recommended for patients with rare

hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose

malabsorption.

Carcinogenesis, Mutagenesis, Impairment of Fertility Positive carcinogenic results were found in two-year carcinogenicity studies with entecavir

conducted in mice and rats. In male mice, increases in the incidences of lung adenomas were

observed at exposures ≥ 3 times the exposure in humans at 1 mg and lung carcinomas were

observed in male and female mice at approximately 40 times the exposure in humans at 1 mg.

Tumor development was preceded by pneumocyte proliferation in the lung, which was not

observed in rats, dogs, or monkeys administered entecavir, indicating that a key event in lung

tumor development observed in mice likely was species specific. Drug-related increased

incidences of other types of tumors were seen at the highest entecavir exposures [in mice

approximately 40 times and in rats 35 times (males) and 24 times (females) human exposure at 1

mg], including liver carcinomas in male mice, benign vascular tumors in female mice, brain

microglial tumors in male and female rats, and liver adenomas and carcinomas in female rats.

Skin fibromas were observed in female rats at both the high (0.4 mg/kg/day; equivalent to 4 times

the exposure in humans at 1 mg) and highest (2.6 mg/kg/day; equivalent to 24 times the exposure

in humans at 1 mg) doses (see TOXICOLOGY, Carcinogenesis, Mutagenesis, Impairment of

Fertility for more detailed information).

It is not known how predictive the results of rodent carcinogenicity studies may be for humans.

Entecavir was clastogenic to human lymphocyte cultures and in mouse lymphoma cells in vitro.

Entecavir was not mutagenic in the Ames bacterial reverse mutation assay, a mammalian-cell

gene mutation assay, and a transformation assay with Syrian hamster embryo cells. Entecavir was

also negative in an oral micronucleus study and an oral DNA repair study in rats. In reproductive

toxicology studies in which rats were administered entecavir at up to 30 mg/kg for up to 4 weeks,


no evidence of impaired fertility was seen in males or females at systemic exposures >90 times

those in humans at 1 mg. In rodent and dog toxicology studies, seminiferous tubular degeneration

was observed at ≥ 35 times the exposure in humans at 1 mg. No testicular changes were evident

in monkeys administered entecavir for 1 year at 167 times the exposure in humans at 1 mg.

Liver Transplant Recipients

The safety and efficacy of entecavir in liver transplant recipients are unknown. The potential for

pharmacokinetic interaction between entecavir and the immunosuppressants cyclosporine A or

tacrolimus was not formally evaluated. If entecavir treatment is determined to be necessary for a

liver transplant recipient who has received or is receiving cyclosporine or tacrolimus, renal

function must be carefully monitored both before and during treatment with entecavir (see

ACTION AND CLINICAL PHARMACOLOGY: Special Populations and DOSAGE AND

ADMINISTRATION: Renal Impairment).

Renal Impairment

Entecavir is predominantly eliminated by the kidney. Dosage adjustment of entecavir is

recommended for patients with a creatinine clearance <50 mL/min, including patients on

hemodialysis or CAPD [continuous ambulatory peritoneal dialysis] (see DOSAGE AND

ADMINISTRATION: Renal Impairment).

Special Populations

Patients co-infected with HIV and HBV:

Entecavir has not been evaluated in patients who are co-infected with HIV and HBV and are not

concurrently receiving effective HIV treatment. Limited clinical experience suggests there is a

potential for the development of resistance to HIV nucleoside reverse transcriptase inhibitors if

entecavir is used to treat chronic hepatitis B virus infection in patients with HIV infection that is

not being treated. Therefore therapy with entecavir is not recommended for HIV/HBV co-

infected patients who are not also receiving highly active antiretroviral therapy (HAART).

Entecavir has not been studied as a treatment for HIV infection and is not recommended for this

use. (See ACTION AND CLINICAL PHARMACOLOGY: Special Populations and Conditions,

Patients Co-infected with HIV and HBV and CLINICAL TRIALS: Special Populations, Patients

Co-infected with HIV and HBV).

Before initiating entecavir therapy, HIV antibody testing should be offered to all patients.

Pregnant Women:

There are no adequate and well-controlled studies in pregnant women. Entecavir should be used

during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Entecavir caused effects on embryo-fetal development in rats at doses that also produced

maternal toxicity; at these doses, exposures to entecavir were 180 times those in humans at 1 mg.

In rabbits, embryo-fetal toxicity was observed at exposures to entecavir 883 times those in

humans at 1 mg. There were no adverse effects on growth, development, and reproductive

performance in the progeny of rats administered entecavir at doses associated with exposures to

entecavir > 94 times those in humans at 1 mg. (see TOXICOLOGY, Reproductive Toxicology

for more detailed information).


Pregnancy Registry:

To monitor maternal-fetal outcomes of pregnant women exposed to entecavir a Pregnancy

Registry has been established. To register patients, physicians must obtain prior consent.

Physicians can register patients by calling 1-800-258-4263.

Labor and Delivery:

There are no studies in pregnant women and no data on the effect of entecavir on transmission of

HBV from mother to infant. Therefore, appropriate interventions should be used to prevent

neonatal acquisition of HBV.

Nursing Women:

Entecavir is excreted in the milk of rats. It is not known whether this drug is excreted in human

milk. Mothers should be instructed not to breast-feed if they are taking entecavir.

Pediatrics (<16 years of age):

Safety and effectiveness of entecavir in pediatric patients below the age of 16 years have not been

established.

Geriatrics (>65 years of age):

Clinical studies of entecavir did not include sufficient numbers of subjects aged 65 years and over

to determine whether they respond differently from younger subjects. Entecavir is substantially

excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with

impaired renal function. Because elderly patients are more likely to have decreased renal

function, care should be taken in dose selection, and it may be useful to monitor renal function

(see DOSAGE AND ADMINISTRATION: Renal Impairment).

Use in Racial/Ethnic Groups:

Clinical studies of entecavir did not include sufficient numbers of subjects from some

racial/ethnic minorities (black/African American, Hispanic) to determine whether they respond

differently to treatment with the drug. There are no significant racial differences in entecavir

pharmacokinetics.

ADVERSE REACTIONS

Adverse Drug Reaction Overview Assessment of adverse reactions is based on four pivotal studies (AI463014, AI463022,

AI463026, and AI463027) in which 1720 patients with chronic hepatitis B infection received

double-blind treatment with entecavir 0.5 mg/day (n=679), entecavir 1 mg/day (n=183), or

lamivudine (n=858) for up to two years (Studies AI463022, AI463027 for nucleoside-naïve

patients and studies AI463014, AI463026 for lamivudine-refractory patients). The safety profiles

of entecavir and lamivudine were comparable in these studies.

The safety profile of entecavir 1 mg (n=51) in HIV/HBV co-infected patients enrolled in Study

AI463038 was similar to that of placebo (n=17) through 24 weeks of blinded treatment and


similar to that seen in non-HIV infected patients. (See WARNINGS AND PRECAUTIONS –

Special Populations: Patients Co-infected with HIV and HBV)

The most common (≥ 3%) adverse events of any severity with at least a possible relation to study

drug for entecavir-treated patients were headache, fatigue, dizziness, and nausea. The most

common adverse events among lamivudine-treated patients were headache, fatigue, and

dizziness. One percent of entecavir-treated patients in these four studies compared with 4% of

lamivudine-treated patients discontinued for adverse events or abnormal laboratory test results.

Clinical Trial Adverse Drug Reactions Because clinical trials are conducted under very specific conditions the adverse reaction

rates observed in the clinical trials may not reflect the rates observed in practice and

should not be compared to the rates in the clinical trials of another drug. Adverse drug

reaction information from clinical trials is useful for identifying drug-related adverse

events and for approximating rates.

Clinical adverse reactions occurring in ≥ 3% of entecavir-treated patients during therapy in four

clinical studies in which entecavir was compared with lamivudine, in addition to selected clinical

adverse reactions that occurred in < 3% of patients are presented in Table 1.

Table 1: Clinical adverse reactions reported in ≥ 3% of entecavir-treated patients, plus selected clinical

adverse reactions in four entecavir clinical trials – through 2 years of treatment

Body System/

Adverse Eventa

Nucleoside-Naiveb Lamivudine-Refractoryc

Entecavir

0.5 mg

n= 679

%

Lamivudine

100 mg

n = 668

%

Entecavir

1 mg

n = 183

%

Lamivudine

100 mg

n = 190

%

Gastrointestinal

Nausea 3 2 4 3

Abdominal pain upper 3 2 2 5

Dyspepsia 2 2 3 <1

Diarrhea 1 <1 2 1

Vomiting 1 <1 1 <1

General

Fatigue 5 5 9 6

Nervous System

Headache 8 8 10 7

Dizziness 4 3 5 2

Somnolence 1 1 2 1

Psychiatric

Insomnia 2 1 1 <1

a Includes events of possible, probable, certain, or unknown relationship to treatment regimen. b Studies AI463022 and AI463027 Mean duration of therapy was 69 weeks for entecavir-treated and 63 weeks for

lamivudine-treated patients. c Includes Study AI463026 and the entecavir 1-mg and lamivudine treatment arms of Study AI463014, a Phase 2

multinational, randomized, double-blind study of three doses of entecavir (0.1, 0.5, and 1 mg) once daily versus

continued lamivudine 100 mg once daily for up to 52 weeks in patients who experienced recurrent viremia on

lamivudine therapy. Mean duration of therapy was 73 weeks for entecavir-treated and 51 weeks for lamivudine-

treated patients.


Exacerbations of Hepatitis After Discontinuation of Treatment

In the Phase 3 studies, a subset of patients was allowed to discontinue treatment at or after 52

weeks if they achieved a protocol-defined response to therapy. An exacerbation of hepatitis or

ALT flare was defined as ALT >10 X ULN and >2 X the patient’s reference level (minimum of

the baseline or last measurement at end of dosing). As demonstrated in Table 2, a proportion of

patients experienced post-treatment ALT flares. If entecavir is discontinued without regard to

treatment response, the rate of post-treatment flares could be higher.

Table 2: Exacerbations of hepatitis during off-treatment follow-up, patients in studies AI463022 , AI463027

and AI463026

Patients with ALT Elevations > 10xULN and >2 x Referencea

Entecavir Lamivudine

Total Nucleoside-naïve

HBeAg-positive

HBeAg-negative

28/476 (6%)

4/174 (2%)

24/302 (8%)

43/417 (10%)

13/147 (9%)

30/270 (11%)

Lamivudine-refractory 6/52 (12%) 0/16 a Reference is the minimum of the baseline or last measurement at end of dosing. Median time to off-treatment

exacerbation was 23 weeks for entecavir-treated patients and 10 weeks for lamivudine-treated patients.

Abnormal Hematologic and Clinical Chemistry Findings Frequencies of selected treatment-emergent laboratory abnormalities reported during therapy in

four clinical trials of entecavir compared with lamivudine are listed in Table 3.

Table 3: Selected treatment-emergenta laboratory abnormalities reported in four entecavir clinical trials -

through 2 years

Test

Nucleoside -Naiveb

Lamivudine-Refractoryc

Entecavir

0.5 mg (n = 679)

Lamivudine

100 mg (n = 668)

Entecavir

1 mg (n = 183)

Lamivudine

100 mg (n = 190)

ALT> 10 x ULN and > 2 x baseline 2% 4% 2% 11%

ALT > 5.0 ULN 11% 16% 12% 24%

AST > 5.0 ULN 5% 8% 5% 17%

Albumin < 2.5 g/dL <1% <1% 0% 2%

Total bilirubin > 2.5 x ULN 2% 2% 3% 2%

Amylase > 2.1 x ULN 2% 2% 3% 3%

Lipase > 2.1 x ULN 7% 6% 7% 7%

Creatinine ≻ 3.0 x ULN 0% 0% 0% 0%

Confirmed creatinine increase ≥

44.2 mmol/L 1% 1% 2% 1%

Hyperglycemia fasting

>13.8 mmol/L 2% 1% 3% 1%

Glycosuriad 4% 3% 4% 6%

Hematuriae 9% 10% 9% 6%

Platelets < 50,000/mm3 <1% <1% <1% <1% a On-treatment value worsened from baseline to Grade 3 or Grade 4 for all parameters except albumin (any on

treatment value <2.5 g/dL), confirmed creatinine increase ≥ 44.2 mmol/L and ALT >10 X ULN and >2 X baseline. b Studies AI463022 and AI463027. Mean duration of therapy was 69 weeks for entecavir-treated and 63 weeks for

lamivudine-treated patients. c Includes Study AI463026 and the entecavir 1-mg and lamivudine treatment arms of Study AI463014, a Phase 2

multinational, randomized, double-blind study of three doses of entecavir (0.1, 0.5, and 1 mg) once daily versus

continued lamivudine 100 mg once daily for up to 52 weeks in patients who experienced recurrent viremia on


lamivudine therapy. Mean duration of therapy was 73 weeks for entecavir-treated and 51 weeks for

lamivudinetreated patients. d Grade 3=3+, large, ≥ 500 mg/dL; Grade 4=4+, marked, severe e Grade 3=3+, large, Grade 4 = ≥ 4+, marked, severe, many

ULN= upper limit of normal.

Among entecavir-treated patients in these studies, on-treatment ALT elevations >10 X ULN and

>2 X baseline generally resolved with continued treatment. A majority of these exacerbations

were associated with a ≥ 2 log10/mL reduction in viral load that preceded or coincided with the

ALT elevation. Periodic monitoring of hepatic function is recommended during treatment.

Post-Market Adverse Drug Reactions The following events have been identified during post-approval use of entecavir. Because reports

are voluntary from a population of unknown size, an estimate of frequency cannot be made, as

well, the existence of underlying medical conditions confounds the assessment of causality.

Gastrointestinal disorders: upper abdominal pain, pancreatitis

Metabolism and nutrition disorders: lactose intolerance. Lactic acidosis has been reported, often

in association with hepatic decompensation, other serious medical conditions, or drug exposures.

Patients with decompensated liver disease may be at higher risk for lactic acidosis.

Hepatobiliary disorders: increased transaminases

Skin and subcutaneous tissue disorders: alopecia, rash

Blood and lymphatic system disorders: leukopenia, neutropenia, platelet count decreased

Immune System Disorders: hypersensitivity and drug hypersensitivity including anaphylactoid

reaction

DRUG INTERACTIONS

Overview Since entecavir is primarily eliminated by the kidneys (see ACTION AND CLINICAL

PHARMACOLOGY: Metabolism and Elimination), coadministration of entecavir with drugs

that reduce renal function or compete for active tubular secretion may increase serum

concentrations of either entecavir or the coadministered drug. In clinical trials, coadministration

of entecavir with lamivudine, adefovir dipivoxil, or tenofovir disoproxil fumarate did not result in

significant drug interactions. The effects of coadministration of entecavir with other drugs that

are renally eliminated or are known to affect renal function have not been evaluated, and patients

should be monitored closely for adverse events when entecavir is coadministered with such

drugs.

The metabolism of entecavir was evaluated in in vitro and in vivo studies. Entecavir is not a

substrate, inhibitor, or inducer of the cytochrome P450 (CYP450) enzyme system. At


concentrations up to approximately 10,000-fold higher than those obtained in humans, entecavir

inhibited none of the major human CYP450 enzymes 1A2, 2C9, 2C19, 2D6, 3A4, 2B6, and 2E1.

At concentrations up to approximately 340-fold higher than those observed in humans, entecavir

did not induce the human CYP450 enzymes 1A2, 2C9, 2C19, 3A4, 3A5, and 2B6. (See ACTION

AND CLINICAL PHARMACOLOGY: Metabolism and Elimination.) The pharmacokinetics of

entecavir are unlikely to be affected by coadministration with agents that are either metabolized

by, inhibit, or induce the CYP450 system. Likewise, the pharmacokinetics of known CYP

substrates are unlikely to be affected by coadministration of entecavir.

Drug-Drug Interactions In clinical studies, the steady-state pharmacokinetics of entecavir and coadministered drug were

not altered in interaction studies of entecavir with lamivudine, adefovir dipivoxil, and tenofovir

disoproxil fumarate.

Drug-Food Interactions Oral administration of 0.5 mg of entecavir with a standard high-fat meal (945 kcal, 54.6 g fat) or

a light meal (379 kcal, 8.2 g fat) resulted in a minimal delay in absorption (1.0-1.5 hour fed vs.

0.75 hours fasted), a decrease in Cmax of 44%-46%, and a decrease in AUC of 18%-20%.

Therefore, entecavir should be administered on an empty stomach (at least 2 hours after a meal

and at least 2 hours before the next meal).

DOSAGE AND ADMINISTRATION

Recommended Dose and Dosage Adjustment The usual recommended dose of Sandoz Entecavir for chronic hepatitis B virus infection in

adults and adolescents 16 years of age or older is 0.5 mg once daily.

For adults and adolescents 16 years of age or older with a history of hepatitis B viremia while

receiving lamivudine or with known lamivudine resistance mutations, the recommended dose of

Sandoz Entecavir is 1 mg (two 0.5 mg tablets) once daily.

Sandoz Entecavir should be administered on an empty stomach (at least 2 hours after a meal and

at least 2 hours before the next meal).

Renal Impairment

In patients with renal impairment, the apparent oral clearance of entecavir decreased as creatinine

clearance decreased. Dosage adjustment is recommended for patients with creatinine clearance

<50 mL/min, including patients on hemodialysis or CAPD (continuous ambulatory peritoneal

dialysis), as shown in Table 4.

Table 4: Recommended dosage of entecavir in patients with renal impairment

Creatinine Clearance (mL/min) Usual Dose (0.5 mg) Lamivudine Refractory (1 mg)

≥ 50 0.5 mg once daily 1 mg once daily

30 to <50

0.25 mg once daily

OR

0.5 mg every 48 hours

0.5 mg once daily

OR

1 mg every 48 hours

10 to <30 0.15 mg once daily 0.3 mg once daily


Creatinine Clearance (mL/min) Usual Dose (0.5 mg) Lamivudine Refractory (1 mg)

OR

0.5 mg every 72 hours OR

1 mg every 72 hours

<10

Hemodialysisa or CAPD

0.05 mg once daily

OR

0.5 mg every 7 days

0.1 mg once daily

OR

1 mg every 7 days a On hemodialysis days, administer after hemodialysis.

Hepatic Impairment

No dosage adjustment is necessary for patients with hepatic impairment.

Duration of Therapy

The optimal duration of treatment with Sandoz Entecavir for patients with chronic hepatitis B

infection and the relationship between treatment and long-term outcomes such as cirrhosis and

hepatocellular carcinoma are unknown.

OVERDOSAGE

For management of a suspected drug overdose, contact your regional Poison Control

Centre.

Activated charcoal may be administered to aid in the removal of unabsorbed drug. General

supportive measures are recommended. Healthy subjects who received single entecavir doses up

to 40 mg or multiple doses up to 20 mg/day for up to 14 days had no increase in, or unexpected,

adverse events. If overdose occurs, the patient must be monitored for evidence of toxicity, and

standard supportive treatment applied as necessary.

Following a single 1-mg dose of entecavir, a 4-hour hemodialysis session removed

approximately 13% of the entecavir dose.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action Entecavir is a guanosine nucleoside analogue that is efficiently phosphorylated to the active

triphosphate form and exhibits selective activity against HBV polymerase, competes with the

natural substrate deoxyguanosine triphosphate, and inhibits all three functional activities of the

HBV polymerase (reverse transcriptase, rt): (1) base priming, (2) reverse transcription of the

negative strand from the pregenomic messenger RNA, and (3) synthesis of the positive strand of

HBV DNA. Entecavir triphosphate has an inhibition constant (Ki) for HBV DNA polymerase of

0.0012 mcM and is a weak inhibitor of cellular DNA polymerases α, ß, and δ and mitochondrial

DNA polymerase γ with Ki values ranging from 18 to >160 mcM.

Antiviral Activity

Entecavir inhibited HBV DNA synthesis (50% reduction, EC50) at a concentration of 0.004 mcM

in human HepG2 cells transfected with wild-type HBV. The median EC50 value for entecavir


against lamivudine resistant HBV (rtL180M, rtM204V) was 0.026 mcM (range 0.010-0.059

mcM).

A comprehensive analysis of the inhibitory activity of entecavir against a panel of laboratory and

clinical HIV-1 isolates using a variety of cells and assay conditions yielded EC50 values ranging

from 0.026 to >10 mcM: the lower EC50 values were observed when decreased levels of virus

were used in the assay. In cell culture, entecavir selected for an M184I substitution in HIV

reverse transcriptase at micromolar concentrations, confirming inhibitory pressure at high

entecavir concentrations. HIV variants containing the M184I substitution showed loss of

susceptibility to entecavir.

The coadministration of HIV nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) with

entecavir is unlikely to reduce the antiviral efficacy of entecavir against HBV or of any of these

agents against HIV. In HBV combination assays in vitro, abacavir, didanosine, lamivudine,

stavudine, tenofovir, or zidovudine were not antagonistic to the anti-HBV activity of entecavir

over a wide range of concentrations. In HIV antiviral assays, entecavir was not antagonistic to the

in vitro anti-HIV activity of these six NRTIs or emtricitabine at concentrations greater than 100

times the Cmax of entecavir using the 1-mg dose.

Drug Resistance

Clinical Studies

In nucleoside-naive studies (AI463022, AI463027, and rollover study AI463901) and in studies

of lamivudine-refractory HBV (AI463026, AI463014, AI463015, and rollover study AI463901),

patients initially treated with entecavir 0.5 mg (nucleoside-naïve) or 1.0 mg (lamivudine

refractory) and with an on-therapy PCR HBV DNA measurement at or after Week 24 were

monitored for resistance. Virologic breakthroughs due to resistance to entecavir are observed in

viruses which harbour primary lamivudine resistance substitutions (M204I/V ± L180M) along

with additional substitutions at residues T184, S202 or M250 of the viral polymerase.

Nucleoside-naïve patients:

Through Year 5, genotypic evidence of entecavir resistance (ETVr) substitutions at residues

T184, S202 or M250 was observed in 3 patients (<1%), 2 of whom experienced virologic

breakthrough (see Table 5). The results reflect use of a 1 mg dose of entecavir in 147 patients in

Year 3 and all patients in Years 4 and 5 and of entecavir-lamivudine combination therapy

(followed by long-term entecavir monotherapy) for a median of 20 weeks for 130 patients in

Year 3 and for 1 week for one patient in Year 4 in a rollover study.

Table 5: Genotypic Entecavir Resistance and Virologic Breakthrough with Resistance Through

Year 5, Nucleoside-Naïve Studies

Year

1

Year

2

Year

3a

Year

4a

Year

5a


Subjects treated and monitored for resistanceb 663 278 149 121 108

Emerging Genotypic ETVc,d 1 1 1 0 0

Genotypic ETVr c,d withVirologic breakthroughe 1 0 1 0 0

Cumulative probability of emerging genotypic ETVr c,d 0.2% 0.5% 1.2% 1.2% 1.2%

Cumulative probability of genotypic ETVr c,d with virologic

breakthroughe

0.2% 0.2% 0.8% 0.8% 0.8%

a Results reflect the use of a 1-mg dose of entecavir for 147 subjects in Year 3 and all subjects in Years 4 and 5 and

of combination entecavir-lamivudine therapy (followed by long-term entecavir therapy) for a median of 20 weeks for

130 subjects in Year 3 and for 1 week for 1 subject in Year 4 in rollover study. b Includes subjects with at least one on-therapy HBV DNA measurement by PCR at or after week 24 through week

58 (Year 1), after week 58 through week 102 (Year 2), after week 102 through week 156 (Year 3), after week 156

through week 204 (Year 4), or after week 204 through week 252 (Year 5). c ETVr = entecavir resistance substitutions at residues T184, S202 or M250. d Subjects also had lamivudine resistance substitutions (rtM204V and rtL180M). e ≥1 log10 increase above nadir in HBV DNA by PCR, confirmed with successive measurements or at the end of the

windowed point.

Emerging amino acid substitutions at M204I/V ± L180M, L80I, or V173L, which conferred

decreased phenotypic susceptibility to entecavir in the absence of S202, T184, or M250 changes,

were detected in the HBV of 3 patients (3/663 = <1%) who experienced virologic breakthrough

by the end of Year 5.

Lamivudine-refractory patients:

Through Year 5, genotypic evidence of entecavir resistance (ETVr) substitutions at residues

T184, S202 or M250 was observed in 47 patients, 39 of whom experienced virologic

breakthrough (see Table 6) The results reflect the use of entecavir-lamivudine combination

therapy (followed by long-term entecavir monotherapy) for a median of 13 weeks for 48 patients

in Year 3, for a median of 38 weeks for 10 patients in Year 4 and for 16 weeks for 1 patient in

Year 5 in a rollover study.

Table 6: Genotypic entecavir resistance and virologic breakthrough with resistance through year 5,

lamivudine-refractory studies

Year

1

Year

2

Year

3a

Year

4a

Year

5a

Subjects treated and monitored for resistanceb 187 146 80 52 33

Emerging Genotypic ETVc,d 11 12 16 6 2

Genotypic ETVr c,d with Virologic breakthroughe 2f 14 f 13 f 9 f 1f

Cumulative probability of emerging genotypic ETVrc,d 6% 15% 36% 47% 51%

Cumulative probability of genotypic ETVrc,d with virologic

breakthroughe 1% f 11% f 27% f 41% f 44% f

aResults reflect the use of combination entecavir-lamivudine therapy (followed by long-term entecavir therapy) for a

median of 13 weeks for 48 subjects in Year 3, for a median of 38 weeks for 10 subjects in Year 4, and for 16 weeks

for 1 patient in Year 5 in a rollover study. bIncludes subjects with at least one on-therapy HBV DNA measurement by PCR at or after week 24 through week 58

(Year 1), after week 58 through week 102 (Year 2), after week 102 through week 156 (Year 3) after week 156

through week 204 (Year 4), or after week 204 through week 252 (Year 5). cETVr = entecavir resistance substitutions at residues T184, S202 or M250. dSubjects also had lamivudine resistance substitutions (rtM204V/I± rtL180M). e≥1 log10 increase above nadir in HBV DNA by PCR, confirmed with successive measurements or at the end of the

windowed point. fETVr occurring in any year, virologic breakthrough in a specified year.


The presence of ETVr substitutions at baseline in isolates from 10 (5%) of 187

lamivudinerefractory patients indicates that prior lamivudine treatment can select these resistance

substitutions and they can exist at a low frequency before entecavir treatment. Through Year 5, 3

of the 10 patients experienced virologic breakthrough. Isolates from patients who experienced

virologic breakthrough with the emergence of S202, T184 and/or M250 substitutions (n=39), had

a median 285 fold-change in entecavir susceptibility as compared to wild type HBV. Three

additional subjects experienced virologic breakthrough with the emergence of M204I/V ±

L180M, L80V or V173L/M alone.

Integrated Analysis of Phase 2 and 3 Clinical Studies

In a post-approval integrated analysis of entecavir resistance data from 17 Phase 2 and 3 clinical

studies, an emergent entecavir resistance-associated substitution rtA181C was detected in 5 out of

1461 subjects during treatment with entecavir. This substitution was detected only in the presence

of lamivudine resistance-associated substitutions rtL180M plus rtM204V.

Cross-resistance

Cross-resistance has been observed among HBV nucleoside analogues. In cell-based assays,

HBV containing lamivudine resistance substitutions M204V/I +/- L180M was 8-fold less

susceptible to entecavir than wild type virus. Further reductions (>70 fold) in entecavir

phenotypic susceptibility required the presence of primary lamivudine resistance amino acid

substitutions (M204V/I +/- L180M ) along with additional substitutions at residues rtT184,

rtS202, or rtM250, or a combination of these substitutions with or without an rtI169 substitution

in the HBV polymerase.

Recombinant HBV genomes encoding adefovir resistance-associated substitutions at either

rtN236T or rtA181V remained susceptible to entecavir. HBV isolates from lamivudine-refractory

patients failing entecavir therapy were susceptible in vitro to adefovir but retained resistance to

lamivudine.

Lamivudine-resistant strains harboring rtL180M plus rtM204V in combination with amino acid

substitution rtA181C conferred 16- to 122-fold reductions in entecavir phenotypic susceptibility.

Pharmacokinetics

The single- and multiple-dose pharmacokinetics of entecavir were evaluated in healthy subjects

and patients with chronic hepatitis B infection (including liver transplant recipients). Steady-state

Pharmacokinetics of entecavir are summarized in Table 7.

Table 7 - Summary of entecavir pharmacokinetic parameters in healthy subjects

Cmax

(ng/mL)

T1/2

(h)

AUC(TAU)1

(ng.h/mL)

Clearance

(CLT/F)

(mL/min)

CLR

(mL/min)

Steady-state mean (0.5 mg) 4.2 130 14.8 572 360

Steady-state mean (1.0 mg) 8.2 149 26.4 636 471 1 Geometric mean

Absorption:


Following oral administration in healthy subjects, entecavir was rapidly absorbed with peak

plasma concentrations occurring between 0.5 and 1.5 hours. Following multiple daily doses

ranging from 0.1 to 1.0 mg, Cmax and area under the concentration-time curve (AUC) at steady

state increased in proportion to dose. Steady state was achieved after 6-10 days of once-daily

administration with approximately 2 fold accumulation. For a 0.5-mg oral dose, Cmax at steady

state was 4.2 ng/mL and trough plasma concentration (Ctrough) was 0.3 ng/mL. For a 1 mg oral

dose, Cmax was 8.2 ng/mL and Ctrough was 0.5 ng/mL.

Effects of food on oral absorption:

Oral administration of 0.5 mg of entecavir with a standard high-fat meal (945 kcal, 54.6 g fat) or

a light meal (379 kcal, 8.2 g fat) resulted in a delay in absorption (1.0-1.5 hours fed vs. 0.75

hours fasted), a decrease in Cmax of 44%-46%, and a decrease in AUC of 18%-20%. Therefore,

entecavir should be administered on an empty stomach (at least 2 hours after a meal and at least 2

hours before the next meal).

Distribution:

Based on the pharmacokinetic profile of entecavir after oral dosing, the estimated apparent

volume of distribution is in excess of total body water, suggesting that entecavir is extensively

distributed into tissues. Protein binding to human serum protein in vitro was approximately 13%.

Metabolism:

The metabolism of entecavir was evaluated in in vitro and in vivo studies. Entecavir is not a

substrate, inhibitor, or inducer of the cytochrome P450 (CYP450) enzyme system. At

concentrations approximately 10,000 fold higher than those obtained in humans, entecavir

inhibited none of the major human CYP450 enzymes 1A2, 2C9, 2C19, 2D6, 3A4, 2B6, and 2E1.

At concentrations approximately 340 fold higher than those observed in humans, entecavir did

not induce the human CYP450 enzymes 1A2, 2C9, 2C19, 3A4, 3A5, and 2B6. Following

administration of 14C-entecavir in humans and rats, no oxidative or acetylated metabolites were

observed. Minor amounts of the phase II metabolites glucuronide and sulfate conjugate were

observed.

Excretion:

After reaching peak concentration, entecavir plasma concentrations decreased in a bi- exponential

manner with a terminal elimination half-life of approximately 128-149 hours.

The observed drug accumulation index is approximately 2 fold with once-daily dosing, indicating

an effective accumulation half-life of approximately 24 hours.

Entecavir is predominantly eliminated by the kidney with urinary recovery of unchanged drug at

steady state ranging from 62% to 73% of the administered dose. Renal clearance is independent

of dose and ranges from 360 to 471 mL/min suggesting that entecavir undergoes both glomerular

filtration and net tubular secretion (see DRUG INTERACTIONS).

Special Populations and Conditions

Patients Co-Infected with HIV and HBV:


Study AI463038 was a randomized, double-blind, placebo-controlled study of entecavir versus

placebo in 68 patients co-infected with HIV and HBV, who experienced recurrence of HBV

viremia while receiving a lamivudine-containing highly active antiretroviral (HAART) regimen.

Patients continued their lamivudine-containing HAART regimen (lamivudine dose 300 mg/day)

and were assigned to add either entecavir 1 mg once daily (51 patients) or placebo (17 patients)

for 24 weeks followed by an open-label phase for an additional 24 weeks where all patients

received entecavir. At baseline, patients had a mean serum HBV DNA level by PCR of 9.13 log10

copies /mL. Ninety-nine percent of patients were HBeAg-positive at baseline, with a mean

baseline ALT level of 71.5 U/L. Median HIV RNA level remained stable at approximately 2

log10 copies/mL through 24 weeks of blinded therapy. Virologic and biochemical endpoints at

Week 24 are shown in Table 8. There are no data in patients with HIV/HBV co-infection who

have not received prior lamivudine therapy. Entecavir has not been evaluated in HIV/HBV co-

infected patients who were not simultaneously receiving effective HIV treatment. (See

WARNINGS AND PRECAUTIONS – Special Populations: Patients Co-Infected with HIV and

HBV)

Table 8: Virologic and Biochemical Endpoints at Week 24, Study AI463038

Entecavir 1 mga

N=51

Placeboa

N=17

HBV DNAb

Proportion undetectable (<300 copies/mL) 6% 0

Mean change from baseline (log10

copies/mL) (-3.65*) (+0.11)

ALT normalization (≤ 1 x ULN) (34%)c (8%)c a All patients also received a lamivudine-containing HAART regimen b Roche COBAS Amplicor PCR assay (LLOQ = 300 copies/mL) c Percentage of patients with abnormal ALT (> 1 x ULN) at baseline who achieved ALT normalization (n=35 for

Entecavir and n=12 for placebo) * p < 0.0001

For patients originally assigned to entecavir, at the end of the open-label phase (Week 48), 8% of

patients had HBV DNA < 300 copies/mL by PCR, the mean change from baseline HBV DNA by

PCR was -4.20 log10 copies/mL, and 37% of patients with abnormal ALT at baseline had ALT

normalization (≤ 1 X ULN).

Pediatrics: Pharmacokinetic studies have not been conducted in children.

Geriatrics: The effect of age on the pharmacokinetics of entecavir was evaluated following administration of

a single 1mg oral dose in healthy young (20–40 years old) and elderly (65-83 years old)

volunteers. Entecavir AUC was 29.3% greater in elderly subjects compared to young subjects.

The disparity in exposure between elderly and young subjects was most likely attributable to

differences in renal function. Dosage adjustment of entecavir should be based on the renal

function of the patient, rather than age (see DOSAGE AND ADMINISTRATION: Renal

Impairment).

Gender / Race:


There are no significant gender/racial differences in entecavir pharmacokinetics.

Hepatic Impairment: No dosage adjustment of entecavir is recommended for patients with hepatic impairment. The

pharmacokinetics of entecavir following a single 1 mg dose were studied in patients (without

chronic hepatitis B infection) with moderate and severe hepatic impairment. The

pharmacokinetics of entecavir were similar between hepatically impaired patients and healthy

control subjects.

Post-Liver Transplant:

The safety and efficacy of entecavir in liver transplant recipients are unknown. However, in a

small pilot study of entecavir use in HBV-infected liver transplant recipients on a stable dose of

cyclosporine A (n=5) or tacrolimus (n=4), entecavir exposure was approximately 2 fold the

exposure in healthy subjects with normal renal function. Altered renal function contributed to the

increase in entecavir exposure in these patients. The potential for pharmacokinetic interactions

between entecavir and cyclosporine A or tacrolimus was not formally evaluated. Renal function

must be carefully monitored both before and during treatment with entecavir in liver transplant

recipients who have received or are receiving an immunosuppressant that may affect renal

function, such as cyclosporine or tacrolimus (see DOSAGE AND ADMINISTRATION: Renal

Impairment).

Renal Insufficiency: The pharmacokinetics of entecavir following a single 1 mg dose were studied in patients (without

chronic hepatitis B infection) with selected degrees of renal impairment, including patients whose

renal impairment was managed by hemodialysis or continuous ambulatory peritoneal dialysis

(CAPD). Results are shown in Table 9.

Table 9: Pharmacokinetic Parameters in Subjects with Selected Degrees of Renal Function

Baseline Creatinine Clearance (mL/min) Severe

Managed

with

Hemodialysisa

(n = 6)

Severe

Managed

with CAPD

(n = 4)

Unimpaired

> 80

(n = 6)

Mild

> 50≤ 80

(n = 6)

Moderate

30-50

(n = 6)

Severe

< 30

(n = 6)

Cmax (ng/mL)

(CV%)

8.1

(30.7)

10.4

(37.2)

10.5

(22.7)

15.3

(33.8)

15.4

(56.4)

16.6

(29.7)

AUC(0-T) (ng·h/mL)

(CV)

27.9

(25.6)

51.5

(22.8)

69.5

(22.7)

145.7

(31.5)

233.9

(28.4)

221.8

(11.6)

CLR (mL/min)

(SD)

383.2

(101.8)

197.9

(78.1)

135.6

(31.6)

40.3

(10.1) NA NA

CLT/F (mL/min)

(SD)

588.1

(153.7)

309.2

(62.6)

226.3

(60.1)

100.6

(29.1)

50.6

(16.5)

35.7

(19.6) a Dosed immediately following hemodialysis

CLR=renal clearance; CLT/F=apparent oral clearance.

Dosage adjustment is recommended for patients with a creatinine clearance <50 mL/min,

including patients on hemodialysis or CAPD. (See DOSAGE AND ADMINISTRATION:

Renal Impairment).

Following a single 1 mg dose of entecavir, hemodialysis removed approximately 13% of the


entecavir dose over 4 hours and CAPD removed approximately 0.3% of the dose over 7 days.

Entecavir should be administered after hemodialysis.

STORAGE AND STABILITY

Store Sandoz Entecavir at room temperature (15° to 30°C).

DOSAGE FORMS, COMPOSITION AND PACKAGING

Sandoz Entecavir tablets contain entecavir as the active ingredient.

Sandoz Entecavir tablets contain the following inactive ingredients: lactose monohydrate,

microcrystalline cellulose, crospovidone, and magnesium stearate. The tablet coating contains

titanium dioxide, hypromellose, polyethylene glycol, and talc.

Sandoz Entecavir is available in the following strength and configurations:

Product Strength and

Dosage Form

Description Quantity

0.5 mg film-coated tablet White, round, film-coated

tablet with debossment on

both sides: “SZ” on one side

and “108” on the other side.

Blister packages containing

30 tablets

HDPE bottles with child-

resistant closures containing

30 or 1000 tablets


PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Entecavir

Chemical name: 2-amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-

methylenecyclopentyl]- 6H-purin-6-one, monohydrate.

Molecular formula and molecular mass: C12H15N5O3•H2O 295.3

Structural formula:

Physicochemical properties: White to off-white powder. It is slightly soluble in water (2.4

mg/mL), and the pH of the saturated solution in water is 7.9 at 25°

± 0.5° C.


CLINICAL TRIALS

Comparative Bioavailability Studies A blind, randomized, single-dose, 2-way crossover comparative bioavailability study of Sandoz

Entecavir 0.5 mg Tablet (test) and Baraclude® 0.5 mg Tablet (reference), was conducted in 15

healthy male subjects (18 to 55 years of age) under fasting conditions. Bioavailability data were

measured and the results are summarized in the following table.

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

Entecavir

(1 x 0.5 mg)

From measured data

Geometric Mean

Arithmetic Mean (CV %)

Parameter Test* Reference† % Ratio of

Geometric Means 90% Confidence Interval

AUC0-72

(pg.h/mL) 12449.93

12704.58 (18.90)

12149.20

12481.32 (22.76)

102.48%

98.10% to 107.05%

Cmax

(pg/mL)

3980.15

4114.65 (24.44)

4141.13

4268.61 (23.54) 96.11% 89.36% to 103.38%

Tmax§

(h) 0.728 (28.85) 0.683 (33.30)

δ Due to the design of the study, AUCI and T1/2

parameters could not be accurately estimated. * Sandoz Entecavir 0.5 mg tablets (Sandoz Canada Inc.). †

Baraclude® 0.5 mg tablets (Bristol-Myers Squibb Canada) were purchased in Canada. §

Expressed as the arithmetic mean (CV%) only.

The safety and efficacy of entecavir were evaluated in three pivotal active-controlled trials on

five continents. These studies included 1633 patients 16 years of age or older with chronic

hepatitis B infection (serum HBsAg-positive for at least 6 months) accompanied by evidence of

viral replication (detectable serum HBV DNA, as measured by the bDNA hybridization or PCR

assay). Subjects had persistently elevated ALT levels ≥ 1.3 times the upper limit of normal

(ULN) and chronic inflammation on liver biopsy compatible with a diagnosis of chronic viral

hepatitis. The safety and efficacy of entecavir were also evaluated in a study of 68 patients co-

infected with HBV and HIV.

Nucleoside-Naive Patients With Compensated Liver Disease, Outcomes at 48 Weeks

HBeAg-positive

Study AI463022 was a multinational, randomized, double-blind study of entecavir 0.5 mg once

daily versus lamivudine 100 mg once daily for a minimum of 52 weeks in 709 (of 715

randomized) nucleoside-naive patients with chronic hepatitis B infection and detectable HBeAg.

The mean age of patients was 35 years, 75% were male, 57% were Asian, 40% were Caucasian,

and 13% had previously received interferon-α. At baseline, patients had a mean Knodell

Necroinflammatory Score of 7.8, mean serum HBV DNA as measured by Roche COBAS

Amplicor® PCR assay was 9.66 log10 copies/mL, and mean serum ALT was 143 U/L. Paired,


adequate liver biopsy samples were available for 89% of patients.

HBeAg-negative (anti-HBe positive/HBV DNA positive)

Study AI463027 was a multinational, randomized, double-blind study of entecavir 0.5 mg once

daily versus lamivudine 100 mg once daily for a minimum of 52 weeks in 638 (of 648

randomized) nucleoside-naive patients with HBeAg-negative (HBeAb-positive) chronic hepatitis

B infection. The mean age of patients was 44 years, 76% were male, 39% were Asian, 58% were

Caucasian, and 13% had previously received interferon-α. At baseline, patients had a mean

Knodell Necroinflammatory Score of 7.8, mean serum HBV DNA as measured by Roche

COBAS Amplicor PCR assay was 7.58 log10 copies/mL, and mean serum ALT level was 142

U/L. Paired, adequate liver biopsy samples were available for 88% of patients.

In Studies AI463022 and AI463027, entecavir was superior to lamivudine on the primary

efficacy endpoint of Histologic Improvement, defined as ≥ 2-point reduction in Knodell

Necroinflammatory Score with no worsening in Knodell Fibrosis Score at Week 48, and on the

secondary efficacy measures of reduction in viral load and ALT normalization. Histologic

Improvement and change in Ishak Fibrosis Score are shown in Table 10. Biochemical, virologic,

and serologic outcome measures are shown in Table 11.

Table 10: Histologic Improvement and Change in Ishak Fibrosis Score at Week 48, Nucleoside-Naive Patients

in Studies AI463022 and AI463027

Study AI463022 (HBeAg-Positive) Study AI463027 (HBeAg-Negative)

Entecavir

0.5 mg

n = 314a

Lamivudine

100 mg

n = 314a

Difference

Entecavir

Lamivudine

(95% CI) b

Entecavir

0.5 mg

n = 296a

Lamivudine

100 mg

n = 287a

Difference

Entecavir

Lamivudine

(95% CI)b

Histologic Improvement (Knodell Scores)

Improvementc 72% 62% 9.9%

(2.6%,

17.2%)

p < 0.01

70% 61%

9.6%

(2.0%,

17.3%)

p < 0.05

No improvement 21% 24% 19% 26%

Ishak Fibrosis Scored

Improvementd 39% 35% 3.2%

(-4.4%,

10.7%)

p= NSe

36% 38% -1.8%

(-9.7%, 6.0%)

p= NSe

No change 46% 40% 41% 34%

Worseningd 8%

10%

12%

15%

Missing Week

48 biopsy

7%

14%

10%

13%

a Patients with evaluable baseline histology (baseline Knodell Necroinflammatory Score ≥ 2). b In these analyses, missing or inadequate biopsies at Week 48 were classified “no improvement.” c ≥ 2-point decrease in Knodell Necroinflammatory Score from baseline with no worsening of the Knodell Fibrosis

Score. d For Ishak Fibrosis Score, improvement = ≥ 1-point decrease from baseline and worsening = ≥ 1-point increase from

baseline. e NS = Not significant.


Table 11: Selected Virologic, Biochemical, and Serologic Endpoints at Week 48, Nucleoside-Naive Patients in

Studies AI463022 and AI463027

Study AI463022 (HBeAg-Positive) Study AI463027 (HBeAg-Negative)

Entecavir

0.5 mg

n = 354

Lamivudine

100 mg

n = 355

Difference

Entecavir

Lamivudine

(95% CI)

Entecavir

0.5 mg

n = 325

Lamivudine

100 mg

n = 313

Difference

Entecavir

Lamivudine

(95% CI)

ALT

normalization

( ≤ 1.0X ULN)

68 % 60 % 8.4 %

1.3%, 15.4%

p = 0.0202

78 % 71% 6.9 %a

0.2, 13.7

p = 0.0451

HBV DNA

Mean change

from baseline by

PCRa (log10

copies/mL)

-6.86 -5.39 -1.5

(-1.8 -1.3)

p < 0.0001

-5.04 -4.53 -0.4

(-0.6 -0.3)

p < 0.0001

Proportion

undetectable

(< 300

copies/mL) by

PCRa, b

67% 36% 30.3%

(23.3%-

37.3%)

p < 0.0001

90% 72% 18.3%

(12.3%,

24.2%)

p < 0.0001

<0.7 MEq/mL

by bDNAc

91% 65% 25.6%

(19.8%,

31.4%)

p < 0.0001

95% 89% 5.9%

(1.8%,

10.1%)

p < 0.01

Loss of HBeAg 22% 20% N/A N/A

HBeAg

seroconversion

21% 18% N/A N/A

a Roche COBAS Amplicor PCR assay. b At Week 24, HBV DNA <300 copies/mL by PCR was observed in 42% of entecavir-treated patients and 25% of

lamivudine-treated patients (p<0.0001) in Study AI463022 and 74% of entecavir -treated patients and 62% of

lamivudine-treated patients (p = 0.0013) in Study AI463027. c Quantiplex bDNA assay.

Histologic improvement was independent of baseline levels of HBV DNA or ALT.

Lamivudine-Refractory Patients, Outcomes at 48 Weeks

Study AI463026 was a multinational, randomized, double-blind study of entecavir in 286 (of 293

randomized) HBeAg-positive patients with lamivudine-refractory chronic hepatitis B infection.

Patients receiving lamivudine at study entry either switched to entecavir 1 mg once daily (with

neither a washout nor an overlap period) or continued on lamivudine 100 mg for a minimum of

52 weeks. The mean age of patients was 39 years, 76% were male, 37% were Asian, 62% were

Caucasian, and 52% had previously received interferon-α. The mean duration of prior lamivudine

therapy was 2.7 years, and 85% had lamivudine resistance mutations at baseline by an

investigational line probe assay. At baseline, patients had a mean Knodell Necroinflammatory

Score of 6.5, mean serum HBV DNA as measured by Roche COBAS Amplicor PCR assay was

9.36 log10 copies/mL, and mean serum ALT level was 128 U/L. Paired, adequate liver biopsy

samples were available for 87% of patients.

Entecavir was superior to lamivudine on a primary endpoint of Histologic Improvement (using

the Knodell Score at Week 48). These results and change in Ishak Fibrosis Score are shown in

Table 12. Table 13 shows selected virologic, biochemical, and serologic endpoints.


Table 12: Histologic Improvement and Change in Ishak Fibrosis Score, and Composite Endpoint at Week 48,

Lamivudine-Refractory Patients in Study AI463026

Study AI463026 (HBeAg-Negative)

Entecavir

1 mg

n = 124a

Lamivudine

100 mg

n = 116a

Difference Entecavir

Lamivudine

(97.5% CI)

Histologic Improvement (Knodell Scores)

Improvementb 55% 28% 27.3%c

(13.6%, 40.9%)

p < 0.0001 No improvement 34% 57%

Ishak Fibrosis Score

Improvementd 34% 16% 17.5%c

(6.8%, 28.2%)e

p < 0.01 No change 44% 42%

Worseningd 11% 26%

Inadequate Week 48

biopsy

2% 1%

Missing Week 48 biopsy 10% 15% a Patients with evaluable baseline histology (baseline Knodell Necroinflammatory Score ≥ 2). b ≥ 2-point decrease in Knodell Necroinflammatory Score from baseline with no worsening of the

Knodell Fibrosis Score. c In this analysis, missing or inadequate biopsies at Week 48 were classified “no improvement.” d For Ishak Fibrosis Score, improvement = ≥1-point decrease from baseline and worsening = ≥ 1-

point increase from baseline. e 95% confidence interval.

Table 13: Selected Virologic, Biochemical, and Serologic Endpoints at Week 48, Lamivudine-Refractory

Patients in Study AI463026

Study AI463026

Entecavir

1 mg

n = 141

Lamivudine

100 mg

n = 145

Difference Entecavir

Lamivudine

(95% CI)

ALT normalization

( ≤ 1.0X ULN)a

61% 15 % 45.8 % b

(35.9 %, 55.8 %)

p < 0.0001

HBV DNA

Mean change from baseline by PCRa

(log10 copies/mL)

-5.1 -0.48 -4.4a

(-4.8, -4.0)

Proportion undetectable

(< 300 copies/mL by PCRa)

19% 1% 17.8%

(11.0, 24.5)

p < 0.0001

<0.7 MEq/mL by bDNAc 66% 6% 60.4%a

(51.8%, 69.1%)

p < 0.0001

Loss of HBeAg 10% 3%

HBeAg seroconversion 8% 3% a Roche COBAS Amplicor PCR assay. b At Week 24, HBV DNA <300 copies/mL by PCR was observed in 7% of entecavir -treated patients and no

lamivudine-treated patients (p=0.0011) in Study AI463026 c Quantiplex bDNA assay.

Histologic improvement was independent of baseline levels of HBV DNA or ALT.


Outcomes Beyond 48 Weeks

The optimal duration of therapy with entecavir is unknown. According to protocol-mandated

criteria in the Phase 3 clinical trials, patients discontinued entecavir or lamivudine treatment after

52 weeks according to a definition of response based on HBV virologic suppression (<0.7

MEq/mL by bDNA assay) and loss of HBeAg (in HBeAg-positive patients) or ALT <1.25 X

ULN (in HBeAg-negative patients) at Week 48. Patients who achieved virologic suppression but

did not have a serologic response (HBeAg-positive) or did not achieve ALT <1.25 X ULN

(HBeAg-negative) continued blinded dosing through 96 weeks or until response was achieved.

These protocol-specified patient management guidelines are not intended as guidance for clinical

practice.

Nucleoside-naive, outcomes beyond 48 weeks: Cumulative confirmed outcomes through Week 96

for all treated patients in studies of nucleoside-naive patients are shown in Table 14.

Table 14: Outcomes Through 96 Weeks, Nucleoside-Naïve Patients in Studies AI463022 and AI463027 (All

Treated)

Study AI463022

(HBeAg-Positive)

Study AI463027

(HBeAg-Negative)

Entecavir

0.5 mg

n=354

Lamivudine

100 mg

n=355

Entecavir

0.5 mg

N=325

Lamivudine

100 mg

n=313

HBV DNAa

Proportion undetectable (< 300 copies/mL)

80%*

39%

94%*

77%

ALT normalization

(≤ 1xULN)

87%* 79% 89% 84%

HBeAg seroconversionb 31%

26%

NA

NA

HBeAg lossb 5%

3%

<1%

<1%

a Roche COBAS Amplicor PCR assay (LLOQ = 300 copies/mL). b through the last observation on or off treatment.

* p<0.01

Among nucleoside-naive HBeAg-positive patients, 243 entecavir-treated and 164 lamivudine-

treated patients continued blinded treatment into year 2 (median duration of therapy was 96

weeks). The proportion of patients with HBV DNA <300 copies/mL by PCR increased from 64%

at Week 48 to 81% at Week 96/EOD [End of Dosing (last observation carried forward) for

patients who discontinued between Weeks 48 and 96] for entecavir-treated patients and remained

stable for lamivudine-treated patients (40% at Week 48 and 39% at Week 96/EOD). For

entecavir-treated patients, ALT normalization (≤1 X ULN) occurred in 66% at Week 48 and 79%

at Week 96/EOD. The percentage of lamivudine-treated patients with ALT normalization was

71% at Week 48 and 68% at Week 96/EOD.

Among nucleoside-naive HBeAg-negative patients, 26 patients continued entecavir treatment and

28 patients continued lamivudine treatment into year 2 (median duration of therapy was 96

weeks). The proportion of patients with HBV DNA <300 copies/mL remained stable in both


treatment groups (entecavir 100% at Week 48 and 96% at Week 96/EOD; lamivudine 64% at

both Week 48 and Week 96/EOD). No patient in either treatment group had ALT normalization

at Week 48, while 27% of entecavir-treated patients and 21% of lamivudine-treated patients

achieved ALT normalization at Week 96/EOD.

Liver biopsy results: Of the 679 entecavir -treated patients in the two nucleoside-naïve studies,

293 (43%) eligible patients enrolled in a long-term rollover study and continued entecavir

therapy. Patients in the rollover study received entecavir 1 mg once daily. Sixty-nine of the 293

patients elected to have a repeat liver biopsy after a total treatment duration of more than 144

weeks (3 years). Fifty-seven patients had both an evaluable baseline and long-term biopsy, with a

median duration of entecavir therapy of 280 weeks (approximately 6 years). Ninety-six percent of

these patients had Histologic Improvement as previously defined (see Table 10, footnote c) and

88% had a ≥ 1-point decrease in Ishak fibrosis score. Of the 43 patients with a baseline Ishak

fibrosis score of ≥ 2, 58% had a ≥ 2-point decrease. At the time of the long-term biopsy, 57

(100%) of patients had HBV DNA < 300 copies/mL and 49 (86%) had serum ALT ≤ 1 X ULN.

Lamivudine-refractory, outcomes beyond 48 weeks: Cumulative confirmed outcomes through

Week 96 for all treated lamivudine-refractory patients are shown in Table 15.

Table 15: Outcomes Through 96 Weeks, Lamivudine Refractory Patients in Study AI463026 (All Treated)

Entecavir

1 mg

n= 141

LAMIVUDINE

100 mg

n=145

HBV DNAa

Proportion undetectable (<300 copies/mL) 30%* <1%

ALT normalization (≤ 1 x ULN) 85%* 29%

HBeAg seroconversionb 17%* 6% a Roche COBAS Amplicor PCR assay (LLOQ = 300 copies/mL). b through the last observation on or off treatment.

*p<0.01

Among lamivudine-refractory patients in Study AI463026, 77 entecavir-treated patients

continued dosing into year 2 (median duration of therapy was 96 weeks). The proportion of

patients with HBV DNA <300 copies/mL increased from 21% at Week 48 to 40% at Week

96/EOD. The proportion of patients with ALT normalization increased from 65% at Week 48 to

81% at Week 96/EOD.

Post-Treatment Follow-up

For the 31% of nucleoside-naive, HBeAg-positive entecavir -treated patients who met response

criteria (virologic suppression by bDNA assay and loss of HBeAg) and discontinued therapy,

response was sustained throughout the 24-week post-treatment follow-up period in 75%. For the

88% of nucleoside-naive, HBeAg-negative entecavir -treated patients who met response criteria

(virologic suppression by bDNA assay and ALT <1.25 X ULN), response was sustained

throughout the 24-week post-treatment follow-up period in 46%. Of the 22 (16%) lamivudine-

refractory patients who met response criteria (virologic response on bDNA assay and loss of

HBeAg) while receiving entecavir, response was sustained throughout the 24-week post-

treatment follow-up period in 11 (50%).


Special Populations

Patients Co-Infected with HIV and HBV

Study AI463038 was a randomized, double-blind, placebo-controlled study of entecavir versus

placebo in 68 patients co-infected with HIV and HBV who experienced recurrence of HBV

viremia while receiving a lamivudine-containing highly active antiretroviral (HAART) regimen.

Patients continued their lamivudine-containing HAART regimen (lamivudine dose 300 mg/day)

and were assigned to add either entecavir 1 mg once daily (51 patients) or placebo (17 patients)

for 24 weeks followed by an open-label phase for an additional 24 weeks where all patients

received entecavir. At baseline, patients had a mean serum HBV DNA level by PCR of 9.13

log10 copies/mL. Ninety-nine percent of patients were HBeAg-positive at baseline, with a mean

baseline ALT level of 71.5 U/L. Median HIV RNA level remained stable at approximately 2

log10 copies/mL through 24 weeks of blinded therapy. Virologic and biochemical endpoints at

Week 24 are shown in Table16. There are no data in patients with HIV/HBV co-infection who

have not received prior lamivudine therapy. Entecavir has not been evaluated in HIV/HBV co-

infected patients who were not simultaneously receiving effective HIV treatment. (See

WARNINGS AND PRECAUTIONS – Special Populations: Patients Co-infected with HIV and

HBV).

Table 16: Virologic and Biochemical Endpoints at Week 24, Study AI463038

Entecavir

1 mga

n = 51

Placeboa

n = 17

HBV DNAb

Proportion undetectable (<300 copies/mL) 6% 0

Mean change from baseline (log10 copies/mL) (-3.65*) (+0.11)

ALT normalization (≤ 1 x ULN) (34%) c (8%) c a All patients also received a lamivudine-containing HAART regimen b Roche COBAS Amplicor PCR assay (LLOQ = 300 copies/mL) c Percentage of patients with abnormal ALT (> 1 x ULN) at baseline who achieved ALT normalization (n=35 for

entecavir and n=12 for placebo)

* p < 0.0001

For patients originally assigned to entecavir, at the end of the open-label phase (Week 48), 8% of

patients had HBV DNA < 300 copies/mL by PCR, the mean change from baseline HBV DNA by

PCR was -4.20 log10 copies/mL, and 37% of patients with abnormal ALT at baseline had ALT

normalization (≤ 1% ULN).

DETAILED PHARMACOLOGY

Mechanism of Action

Entecavir is a guanosine nucleoside analogue that is efficiently phosphorylated to the active

triphosphate form and exhibits selective activity against HBV polymerase. Entecavir triphosphate

competes with the natural substrate deoxyguanosine triphosphate, and inhibits all three functional

activities of the HBV polymerase (reverse transcriptase, rt): (1) base priming, (2) reverse

transcription of the negative strand from the pregenomic messenger RNA, and (3) synthesis of

the positive strand of HBV DNA. Entecavir triphosphate has an inhibition constant (Ki) for HBV

DNA polymerase of 0.0012 mcM and is a weak inhibitor of cellular DNA polymerases α, ß, and


δ and mitochondrial DNA polymerase γ with Ki values ranging from 18 to >160 mcM.

Antiviral Activity

Entecavir inhibited HBV DNA synthesis (50% reduction, EC50) at a concentration of 0.004 mcM

in human HepG2 cells transfected with wild-type HBV. The median EC50 value for entecavir

against lamivudine-resistant HBV (rtL180M, rtM204V) was 0.026 mcM (range 0.010-0.059

mcM).

A comprehensive analysis of the inhibitory activity of entecavir against a panel of laboratory and

clinical HIV-1 isolates using a variety of cells and assay conditions yielded EC50 values ranging

from 0.026 to >10 mcM: the lower EC50 values were observed when decreased levels of virus

were used in the assay. In cell culture, entecavir selected for an M184I substitution in HIV

reverse transcriptase at micromolar concentrations, confirming inhibitory pressure at high

entecavir concentrations. HIV variants containing the M184I substitution showed loss of

susceptibility to entecavir.

Daily or weekly entecavir treatment significantly reduced viral DNA levels (4 to 8 log10) in two

relevant animal models, woodchucks chronically infected with woodchuck hepatitis virus (WHV)

and ducks infected with duck HBV. Long-term studies in woodchucks demonstrated that oral

weekly dosing of 0.5 mg/kg entecavir (similar exposure to the 1 mg human dose) maintained

viral DNA levels at undetectable levels (<200 copies/mL by PCR) for up to 3 years in 3 of 5

woodchucks. No entecavir resistance changes were detected in the HBV polymerase in any of the

treated animals for up to 3 years of treatment.

TOXICOLOGY

Acute Toxicity (Table 1)

Single-dose oral toxicity studies with entecavir were conducted in mice and rats at doses ranging

from 40 to 5000 mg/kg. In mice, no drug-related changes were noted at 40 mg/kg. Body-weight

losses were noted at ≥ 200 mg/kg. At ≥1000 mg/kg, signs of overt toxicity and deaths were

observed. In rats, no drug-related changes were observed at doses of 40 or 200 mg/kg. Deaths

occurred at ≥ 1000 mg/kg.

Repeat-Dose Toxicity (Table 2)

Repeat-dose studies utilizing once daily oral dosing were conducted in mice, rats, dogs, and

monkeys. Pivotal studies included two 6-month oral studies each in mice and rats to assess

chronic toxicity and to aid in the selection of doses for oral carcinogenicity studies; two 3-month

studies in dogs to assess toxicity and reversibility of drug-related changes, and a 1-year toxicity

study in monkeys that included a 3-month interim evaluation.

In dogs, species-specific, reversible CNS inflammation was observed at doses that achieved ≥ 51

times the exposure to entecavir in humans at 1 mg. The species-specificity, reversibility, and high

exposure multiples at which the CNS inflammation was observed suggest that this finding is not

relevant to human safety. Other target organs in repeat-dose studies in animals were the kidneys,

liver, lungs, skeletal muscle and testis; the changes in these organs were considered unlikely to be


relevant to human safety because they were either species-specific, associated with high exposure

multiples relative to humans, and/or, in clinical trials with entecavir, they were not target tissues.

With regard to target-organ toxicity in general, the results of a 1-year study in monkeys were

most compelling because no target organ toxicity was evident at ≥ 136 times the exposure to

entecavir in humans at 1 mg.

Reproductive Toxicology (Table 3)

Reproductive toxicology studies were conducted with entecavir to assess potential effects on

embryonic and fetal development in rats and rabbits and on growth, development, and

reproductive performance of progeny in rats.

In rats and rabbits, no embryotoxicity or maternal toxicity was observed at 28 and 212 times,

respectively, the exposure to entecavir at 1 mg in humans. In rats, maternal toxicity, embryo-fetal

toxicity (resorptions), and associated decreases in live-litter size occurred at 180 times the

exposure in humans at 1 mg. Additional findings in rat fetuses at 3100 times the exposure in

humans at 1 mg included lower body weights, tail and vertebral malformations, reduced

ossification (vertebrae, sternebrae, and phalanges), and extra lumbar vertebrae and ribs. In

rabbits, embryo-fetal toxicity (resorptions), reduced ossification (hyoid), and an increased

incidence of 13th rib were observed at 883 times the exposure in humans at 1 mg. In a peri-

postnatal study in rats, no adverse effects on offspring were seen at > 94 times the exposure in

humans at 1 mg.

Carcinogenesis, Mutagenesis, Impairment of Fertility (Tables 4 & 5)

Long-term oral carcinogenicity studies of entecavir in mice and rats were carried out at exposures

up to approximately 42 times (mice) and 35 times (rats) those observed in humans at 1 mg.

MICE: Lung adenomas were increased in males and females at exposures 3 and 40 times those

in humans at 1 mg, respectively. Lung carcinomas in both male and female mice were increased

at exposures approximately 40 times those in humans at 1 mg. Lung tumor development was

preceded by pneumocyte proliferation in the lung, which was not observed in rats, dogs, or

monkeys administered entecavir, indicating that a key event in lung tumor development observed

in mice likely was species specific. At the highest dose level tested (equivalent to approximately

40 times the exposure in humans at 1 mg) hepatocellular carcinomas and the combined incidence

of adenomas and carcinomas in male mice and vascular tumors (hemangiomas of ovaries and

uterus and hemangiomas/hemangiosarcomas of spleen) in female mice were significantly

increased.

The NOEL for neoplasia was 0.004 mg/kg/day for males (equivalent to 1-times the exposure in

humans at 1 mg), based on pulmonary adenomas; for all other tumors in male and female mice

the NOEL was 0.4 mg/kg (equivalent to 14 and 11 times the exposure in humans at 1 mg for

male and female mice, respectively). At tumorigenic doses, systemic exposures were 3-times

(pulmonary tumors in male mice) and approximately 40-times (all other tumors) that in humans

at 1 mg daily.

RATS: In female rats, hepatocellular adenomas and the combined incidence of adenomas and

carcinomas were significantly increased at the highest dose level, equivalent to 24-times the


exposure in humans at 1 mg. Brain microglial tumors were significantly increased in both male

and female rats at the highest dose, equivalent to 35 and 24 times exposure in humans at 1 mg

respectively. Skin fibromas in female rats were significantly increased at the 0.4 (high) and 2.6

mg/kg/day (highest) doses, equivalent to 4 and 24 times exposure in humans at 1 mg

respectively.

The NOEL for neoplasia was 0.2 mg/kg/day for males (equivalent to 5 times the exposure in

humans at 1 mg) and for females 0.06 mg/kg/day based on skin fibromas (equivalent to < 1 times

the exposure in humans at 1 mg) or 0.4 mg/kg/day (all other tumors, equivalent to 4 times the

exposure in humans at 1 mg). At tumorigenic doses, systemic exposures were 35 and 4/24 times

that in humans at 1 mg in male and female rats, respectively.

It is not known how predictive the results of rodent carcinogenicity studies may be for humans.

Entecavir was clastogenic to human lymphocyte cultures and in mouse lymphoma cells in vitro.

Entecavir was not mutagenic in the Ames bacterial reverse mutation assay, a mammalian-cell

gene mutation assay, and a transformation assay with Syrian hamster embryo cells. Entecavir was

also negative in an oral micronucleus study and an oral DNA repair study in rats. In reproductive

toxicology studies in which rats were administered entecavir at up to 30 mg/kg for up to 4 weeks,

no evidence of impaired fertility was seen in males or females at systemic exposures >90 times

those in humans at 1 mg. In rodent and dog toxicology studies, seminiferous tubular degeneration

was observed at ≥ 35 times the exposure in humans at 1 mg. No testicular changes were evident

in monkeys administered entecavir for 1 year at 167 times the exposure in humans at 1 mg.

Table 1 - ACUTE TOXICITY

Species/

Strain

N/Dose/

Sex

Dose

mg/kg/day

Route of

Administration

Observed

Maximum

Non-

Lethal

Dose

(mg/kg)

Approximate

Lethal Dose

(mg/kg)

Findings

Mouse/CD-

1

M5 F5

0, 40, 200,

1000, &

5000

Oral, gavage

200

≥ 1000

40 mg/kg: No drug-related findings.

≥ 200 mg/kg: Transient body-weight

losses.

≥ 1000 mg/kg: One male at 1000

mg/kg and 4 males and all females at

5000 mg/kg died. In the testis,

moderate degeneration of

seminiferous tubular epithelium. In the

spleen, mild to moderate lymphoid

depletion.

Rat/SD

M5

0, 40, 200,

1000, &

5000

Oral, gavage

200

≥ 1000

≤ 200 mg/kg: No drug-related

findings.

≥ 1000 mg/kg: One rat at 1000 mg/kg

and all rats at 5000 mg/kg died. In rats

that died, red discoloration of small

intestine associated with hemorrhage,

and necrosis of duodenum and

jejunum.


Table 2 – REPEAT-DOSE TOXICITY

Species/Strain N/Sex Dose

mg/kg/day

Route of

Administration

Duration

of

Dosing

NOAEL

(mg/kg)

Findings

MOUSE

Mouse/CD-1 Four groups

of 10M 10F

each

0, 0.2, 1, & 5 Oral, gavage 6 months < 0.2 ≥ 0.2 mg/kg: In the liver,

minimal to moderate

centrilobular degeneration.

≥ 1 mg/kg: In the lung,

minimal to mild alveolar

histiocytosis. In skeletal

muscle, minimal to mild

myopathy.

5 mg/kg: Lower body weight

(males); minimal to moderate

decreases in total leukocyte

and lymphocyte counts; mild

to moderate increases in

serum ALT and/or AST;

increased kidney and

decreased testes weights in

males; and minimal to mild

centrilobular hepatocellular

hypertrophy in the liver.

Mouse/CD-1

Three

groups of

10 M 10F

each

0, 10, & 20 Oral, gavage 6 months < 10 ≥ 10 mg/kg: Mortality; lower

body weights, minimal to

mild decreases in serum total

protein, albumin, and

globulins; decreased weights

of the testes and

prostate/seminal vesicles;

increased severity of

nephropathy in the kidneys;

minimal to moderate

degeneration and

hypertrophy in the

centrilobular region of the

liver; bronchioloalveolar

hyperplasia and/or

adenomas, and minimal to

moderate alveolar

histiocytosis in the lungs;

minimal to moderate skeletal

muscle myopathy; and

minimal to moderate

seminiferous-tubular

degeneration in the testes.

20 mg/kg: Mild decreases in

total leukocyte and

lymphocyte counts in males;

and minimal to mild

decreases in serum total


globulins.

RAT

Rat/SD

Four groups

of

0, 0.02, 0.08,

& 0.3

Oral, gavage

6 months

< 0.02

≥ 0.02 mg/kg: Minimal

centrilobular degeneration in



mg/kg/day

Route of

Administration

Duration

of

Dosing

NOAEL

(mg/kg)

Findings

20M 20F

each

the liver.

Rat/SD

Four groups

of 20M 20F

each

0, 0.6, 3, &

15

Oral, gavage 6 months 0.6 ≥ 0.6 mg/kg: Minimal to

mild decreases in serum total


globulins in males; minimal

to mild centrilobular

degeneration in the liver

(associated with enlarged

hepatocellular mitochondria

in males; clearly different

than the hepatocellular

megamitochondria reported

for another antiviral

nucleoside analog and

considered secondary to the

hepatocellular degeneration);

and minimal to mild skeletal-

muscle myopathy.

≥ 3 mg/kg: Minimal to mild

increases in serum urea

nitrogen and cholesterol and

minimal to moderate

increases in serum AST in

males.

15 mg/kg: Lower body

weight in males; mild

increase in total leukocyte

count in males; minimal to

mild increases in

prothrombin time; minimal

to mild increases in serum

urea nitrogen, cholesterol,

and sodium in females;

minimal to mild increases in

serum ALT and chloride;

mild increases in water

consumption and urine

volume and a mild decrease

in urine specific gravity in

males; and decreased testes

weight and size.

DOG

Dog/Beagle Four groups

of 3M 3F

each

0, 0.3, 3, &

30/15 (due to

overt toxicity

at 30 mg/kg,

the high dose

was reduced

to 15 mg/kg

on dose day

29.)

Oral, capsule 3 months < 0.3 ≥ 0.3 mg/kg: Decreased

weights of the testes and

prostrate; and minimal to

moderate inflammation in the

brain.

≥ 3 mg/kg: Decreased

weights of the ovaries;

minimal to mild

inflammation in the spinal

cord; inflammation and

depletion of zymogen

granules in the pancreas;



mg/kg/day

Route of

Administration

Duration

of

Dosing

NOAEL

(mg/kg)

Findings

degeneration of seminiferous

tubules in the testes; and

atrophy in the prostate.

30/15 mg/kg: Three dogs

sacrificed in moribund

condition after

approximately 1 month of

dosing. In surviving high-

dose dogs: clinical signs of

toxicity, clinical laboratory

changes including mild to

moderate decreases in

RBC/WBC parameters and

platelet counts; a mild

increase in serum gamma

glutamyl transferase;

increased myeloid/erythroid

ratio and a moderately

reduced number of

megakaryocytes in bone-

marrow smears; and a

moderate increase in urine

specific gravity. In sacrificed

and surviving dogs:

myeloid/erythroid depletion

in the bone marrow; and

lymphoid depletion in lymph

nodes.

Dog/Beagle Control 4M

4F; 0.1

mg/kg 3M

3F; 15

mg/kg 6M

6F.

2M 2 F

control and

3M 3F at

15 mg/kg

evaluated

after 3-

month

postdose

period.

0, 0.1, & 15 Oral, capsule 3 months 0.1 0.1 mg/kg: No drug-related

changes.

15 mg/kg: Changes generally

were consistent with those at

30/15 mg/kg in the initial 3-

month study, but target

organs were limited to CNS,

pancreas, and testes; all

changes were reversible or

showed evidence of

reversibility (testes weight).

MONKEY

Monkey/Cynomolgus Four groups

of

6M 6F

each; 2M

2F used for

interim

evaluation

after 3

months of

dosing

0, 0.4, 4, &

40

Oral, gavage 1 year 40 0.4 and 4 mg/kg: No drug-

related changes.

40 mg/kg: Minimal increases

in serum urea nitrogen and

potassium.


Table 3 – REPRODUCTION AND TERATOLOGY

Study Type

Species/Strain

N/ Sex Dose

mg/kg/day

(multiple

of human

exposure

Duration of

dosing

Route of

Administration

Findings

Oral Study of

Fertility and Early

Embryonic

Development-

Treated Female Rats

Rats/SD

Four

groups

of 25 F

each

0, 0.3, 3, &

30

2 Weeks

premating

through

Gestation Day

7

Oral, gavage ≥ 0.3 mg/kg: No drug-related changes.

Oral Study of

Fertility and Early

Embryonic

Development-

Treated Male Rats

Rats/SD

Four

groups

of 25 M

each

0, 0.1, 1, &

10

4 Weeks

premating until

scheduled

euthanasia (33

to 42 daily

doses)

Oral, gavage 0.1 and 1 mg/kg: No drug-related

changes.

10 mg/kg: Decreased body weight and

body-weight gain.

Oral Study of

Embryo-Fetal

Development in Rats

Rats/SD

Four

groups

of 22 F

each

0, 2, 20, &

200

Gestation Days

6-15

Oral, gavage 0.2 mg/kg: No drug-related changes.

≥ 20 mg/kg: In the dams: lower body

weights and bodyweight gains. In the

fetuses: increases in embryo-fetal death

(resorptions) with associated decreases

in livelitter sizes.

200 mg/kg: In the dams: 1 death,

decreased food consumption, and

increased incidence of reduced/absent

feces. In the fetuses: lower body weight;

tail and vertebrae malformations; delays

in ossification of the vertebrae,

sternebrae and phalanges; and increases

in the number of lumbar vertebrae and

ribs.

Oral Study of

Embryo-Fetal

Development in

Rabbits Rabbit/NZW

Four

groups

of 20 F

each

0, 1, 4, &

16

Gestation Days

6-18

Oral, gavage 1 and 4 mg/kg: No drug-related changes.

16 mg/kg: In the fetuses: increases in

embryo-fetal death (resorptions) with

associated decreases in live-litter sizes;

developmental delays in ossification of

the hyoid; and an increased incidence of

13th rib.

Oral Study of Pre-

and Postnatal

Development in Rats

Rats/SD

Four

groups

of 25 F

each

0, 0.3, 3, &

30

Gestation Day

6 through Day

20 of Lactation

Oral, gavage 0.3 and 3 mg/kg: No drug-related

changes.

30 mg/kg: In the dams: reduced body-

weight gain.

Table 4 – CARCINOGENICITY

Species/Strain N/ Sex Dose

mg/kg/day

Route of

administration

Duration of

Dosing

Findings

Carcinogenicity

Study in Mice

Mouse/CD-1

Four

groups

of

60M,

60F

each

0, 0, 0.004,

0.04, 0.4, &

4

Oral, gavage 24 months 0.004 mg/kg: No drug-related changes.

≥ 0.04 mg/kg: Increased incidences of

bronchiolo/alveolar adenoma in the lungs in

males.

≥ 0.4 mg/kg: Increased mortality; hyperplasia

of alveolar epithelium,


Species/Strain N/ Sex Dose

mg/kg/day

Route of

administration

Duration of

Dosing

Findings

leukocytosis/interstitial inflammation, and

infiltration of the alveolar spaces by alveolar

macrophages in the lungs.

4 mg/kg: Lower body weights and body-

weight gains; increased incidences of focal

hyperplasia of bronchiolar epithelium and

alveolar fibrosis in the lungs and hematocyts,

thrombi and ectasia in the ovaries; and

increased tumor incidences including:

bronchiolo/alveolar carcinoma in the lung,

bronchiolo/alveolar adenoma (females) in the

lungs, hepatocellular carcinoma (males) in the

liver, and vascular tumors (females).

Carcinogenicity

Study in Rats

Rat/SD

Six

groups

of

60M,

60F

each

0, 0, 0.003,

0.02, & 0.2,

and 1.4 (M);

0, 0, 0.01,

0.06, 0.4, &

2.6 (F)

Oral, gavage 24 months 0.003 mg/kg (males) and 0.01 and 0.06 mg/kg

(females): No drug-related changes.

≥ 0.2 mg/kg (males): Increased incidences of

focal hyperplasia in the acinar (exocrine)

pancreas and hepatocellular alterations in the

liver.

1.4 mg/kg (males): Decreased body weight;

increased incidences of hepatocellular

vacuolation, testicular degeneration, and

chronic progressive nephropathy; and

increased tumor incidences including

malignant glioma in the brain.

≥0.4 mg/kg (females): Increased incidences of

hepatocellular alterations.

2.6 mg/kg (females): Increased incidence of

hepatocellular vacuolation; and increased

tumor incidences including hepatocellular

adenoma carcinoma malignant glioma in the

brain, and skin fibroma.

Table 5 – MUTAGENICITY

Test/Test System Sex Concentration/Dose Route of

Administration

Duration of

Dosing

Effects

IN VITRO

Ames/S. typhimurium

and E. Coli

NA 312.5 to 5000 ng/plate,

both with and without

metabolic activation

NA 48 hr Not mutagenic

Gene Mutation/CHO

cells-HGPRT locus

NA 50 to 1000 mcg/mL

without metabolic

activation

NA 4 hr Not mutagenic when tested to

cytotoxic concentrations

Cytogenetics/Primary

Human Lymphocytes

NA 2.5 to 20 mcg/mL

(without metabolic

activation) and 2.5 to 200

mcg/mL with metabolic

activation

NA 24 hr without

metabolic

activation

and 5 hr with

metabolic

activation

Cytotoxicity at ≥ 5 mcg/mL

(without metabolic

activation) and at 200

mcg/mL (with metabolic

activation. Increased

chromosome aberrations at ≥

10 mcg/mL (without

metabolic activation) and at ≥

50 mcg/mL with metabolic

activation.


Cell

transformation/Syrian

hamster embryo cells

NA 0.125 to 2.0 mcg/mL NA 7 days No increase in

morphologically transformed

cells when tested to cytotoxic

concentrations

IN VIVO

Micronucleus/Rat Male 2 to 2000 mg/kg daily Oral, gavage 3 days Not genotoxic

DNA Repair/Rat Male 2 to 2000 mg/kg Oral, gavage Single Dose Not genotoxic


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11. Chang TT, Gish RG, et al. A comparison of Entecavir and Lamivudine for HBeAg-

Positive Chronic Hepatitis B. N ENGL J MED 2006, 354;10. 1001-1010

12. Lai C-L, Shouval D, et al. Entecavir versus Lamivudine for Patients with HBeAG-


Negative Chronic Hepatitis B. N ENGL J MED 2006, 354; 10. 1011 – 1020

13. Sherman M. et al. Entecavir for Treatment of Lamivudine-Refractory, HBeAg-Positive

Chronic Hepatitis B. Gastro 2006, 130: 2039-2049.

14. Bristol-Myers Squibb Canada. Product Monograph, BARACLUDE®, Control No.:

217518, Date of Revision: August 27, 2018.

IMPORTANT: PLEASE READ


PART III: CONSUMER INFORMATION

PrSandoz Entecavir

Entecavir Tablets

This leaflet is part III of a three-part "Product Monograph"

published when Sandoz Entecavir was approved for sale in

Canada and is designed specifically for Consumers. This leaflet

is a summary and will not tell you everything about Sandoz

Entecavir Contact your doctor or pharmacist if you have any

questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for:

Sandoz Entecavir is a prescription medicine used for chronic

infection with hepatitis B virus (HBV) in adults who also have

active liver damage.

What it does:

• Sandoz Entecavir may lower the amount of HBV in the body

• Sandoz Entecavir may lower the ability of HBV to multiply and

infect new liver cells

• Sandoz Entecavir may reduce the damage to the liver by HBV

Sandoz Entecavir will not cure HBV infection.

It is important to stay under your healthcare provider’s care while

taking Sandoz Entecavir. Your healthcare provider will test the

level of the hepatitis B virus in your blood regularly.

When it should not be used:

Do not take Sandoz Entecavir if you are allergic to any of its

ingredients. The active ingredient in Sandoz Entecavir is entecavir.

See “What the nonmedicinal ingredients are” for a complete list of

ingredients in Sandoz Entecavir.

Tell your healthcare provider if you think you have had an allergic

reaction to any of these ingredients.

Sandoz Entecavir has not been studied in children and is not

recommended for anyone less than 16 years old.

What the medicinal ingredient is:

Entecavir

What the ,mnonmedicinal ingredients are:

Lactose monohydrate, microcrystalline cellulose, crospovidone,

and magnesium stearate. The tablet coating contains titanium

dioxide, hypromellose, polyethylene glycol, and talc.

What dosage forms it comes in:

Sandoz Entecavir is available as a 0.5 mg film-coated tablet.

Does Sandoz Entecavir lower the risk of passing HBV

to others?

Sandoz Entecavir does not stop you from spreading HBV to others

by sex, sharing needles, or being exposed to your blood. Talk to

your healthcare provider about safe sexual practices that protect

your partner. Never share needles. Do not share personal items that

can have blood or body fluids on them, like toothbrushes or razor

blades. A shot (vaccine) is available to protect people at risk from

becoming infected with HBV.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

Severe worsening of hepatitis (liver inflammation) has occurred

in patients who have stopped taking anti-hepatitis B therapy

(including Sandoz Entecavir). Your doctor will monitor your

condition in this case and may resume therapy.

Lactic acidosis (increase in acid level of blood) and severe

hepatomegaly with steatosis (enlarged fatty liver), including fatal

cases have been reported in patients using nucleoside analogue

medicines , including Sandoz Entecavir, either alone or in

combination. Reports of lactic acidosis with

entecavir often involved patients who were seriously ill due to

their liver disease or other medical condition. Lactic acidosis is a

medical emergency and must be treated in the hospital. Call your

healthcare provider right away if you get any of the signs of

lactic acidosis (see table Serious Side Effects and What to do

About them).)

Your hepatitis B infection may get worse or become very serious

if you stop Sandoz Entecavir.

• take Sandoz Entecavir exactly as prescribed

• do not run out of Sandoz Entecavir

• do not stop Sandoz Entecavir without talking to

your healthcare provider

Your healthcare provider will need to monitor your health and do

regular blood tests to check your liver if you stop Sandoz

Entecavir. Tell your healthcare provider right away about any

new or unusual symptoms that you notice after you stop taking

Sandoz Entecavir.

If you have or get HIV (human immunodeficiency virus) infection

be sure to discuss your treatment with your doctor. If you are

taking Sandoz Entecavir to treat chronic hepatitis B and are not

taking medicines for your HIV at the same time, some HIV

treatments that you take in the future may be less likely to work.

You are advised to get an HIV test before you start taking Sandoz

Entecavir and anytime after that when there is a chance you were

exposed to HIV. Sandoz Entecavir will not help your HIV

infection.

BEFORE you use Sandoz Entecavir talk to your healthcare

provider about all of your medical conditions, including if you:

• have had a liver transplant.

• have kidney problems. Your doctor may need to adjust

your Sandoz Entecavir dose or dose schedule.

• are pregnant or planning to become pregnant. It is not

known if Sandoz Entecavir is safe to use during

pregnancy. It is not known whether Sandoz Entecavir

helps prevent a pregnant mother from passing HBV to her

baby. You and your healthcare provider will need to

decide if Sandoz Entecavir is right for you. If you use

Sandoz Entecavir while you are pregnant, talk to your



healthcare provider about the Sandoz Entecavir Pregnancy

Registry.

• are breast-feeding. It is not known if Sandoz Entecavir can

pass into your breast milk or if it can harm your baby. Do

not breast-feed if you are taking Sandoz Entecavir.

• are lactose intolerant. Sandoz Entecavir tablets contain

lactose. If you have been told that you have intolerance to

some sugars, contact your doctor before taking this

medicine.

Tell your healthcare provider about all the medicines you take

including prescription and non-prescription medicines, vitamins,

and herbal supplements. Sandoz Entecavir may interact with other

medicines that leave the body through the kidneys.

Know the medicines you take. Keep a list of your medicines with

you to show your healthcare provider and pharmacist.

INTERACTIONS WITH THIS MEDICATION

Sandoz Entecavir may interact with other medicines that leave the

body through the kidneys.

PROPER USE OF THIS MEDICATION

Take Sandoz Entecavir exactly as prescribed. Your healthcare

provider will tell you how much Sandoz Entecavir to take. Your

dose will depend on whether you have been treated for HBV

infection before and what medicine you took.

Usual dose:

The usual dose of Sandoz Entecavir Tablets in adults and children

over 16 years of age is either one or two 0.5 mg tablets once daily

by mouth. Your dose may be lower or you may take Sandoz

Entecavir less often than once a day, if you have kidney problems.

• Take Sandoz Entecavir once a day on an empty stomach

to help it work better. Empty stomach means at least 2

hours after a meal and at least 2 hours before the next

meal. To help you remember to take your Sandoz

Entecavir, try to take it at the same time each day.

• Do not change your dose or stop taking Sandoz Entecavir

without talking to your healthcare provider. Your

hepatitis B symptoms may get worse or become serious if

you stop taking Sandoz Entecavir. After you stop taking

Sandoz Entecavir, it is important to stay under your

healthcare provider’s care. Your healthcare provider will

need to do regular blood tests to check your liver.

• When your supply of Sandoz Entecavir starts to run low,

get more from your healthcare provider or pharmacy. Do

not run out of Sandoz Entecavir.

Overdose:

If you think you have used too much Sandoz Entecavir, contact

your healthcare professional, hospital emergency department or

regional poison control centre immediately, even if there are no

symptoms.

Missed Dose:

If you forget to take Sandoz Entecavir, take it as soon as you

remember and then take your next dose at its regular time. If it is

almost time for your next dose, skip the missed dose. Do not take

two doses at the same time. Call your healthcare provider or

pharmacist if you are not sure what to do.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

The most common side effects of Sandoz Entecavir are headache,

tiredness, dizziness, and nausea. Rash has also been reported.

Less common side effects include diarrhea, indigestion, vomiting,

sleepiness, and trouble sleeping. In some patients, the results of

blood tests that measure how the liver or pancreas is working may

worsen.

SERIOUS SIDE EFFECTS AND WHAT TO DO ABOUT

THEM

Symptom / effect Talk with your

doctor or

pharmacist

Stop taking

drug and

call your

doctor or

pharmacist Only if

severe

In all

cases

Lactic acidosis (high level of

lactic acid in the blood)

Symptoms:

Feeling very weak or tired

Unusual (not normal) muscle

pain

Trouble breathing

Stomach pain with nausea and

vomiting

Feeling cold especially in arms

and legs

Feeling dizzy or lightheaded

Fast or irregular heartbeat

Worsening hepatitis

(inflamed liver), liver

enlargement (hepatomegaly)

or fatty liver

Symptoms:

Skin or the white part of eyes

turn yellow (jaundice)

Dark urine

Bowel movements (stools)

turn light in colour

Nausea

Lower stomach pain

Loss of appetite for several

days or longer

This is not a complete list of side effects. For any unexpected

effects while taking Sandoz Entecavir, contact your doctor or

pharmacist.

HOW TO STORE IT

Store Sandoz Entecavir tablets at room temperature (between



15°C and 30°C).

Do not store Sandoz Entecavir in a damp place such as a bathroom

medicine cabinet or near the kitchen sink.

Keep the container tightly closed.

Discard Sandoz Entecavir when it is outdated or no longer needed

by returning the unused portion to your pharmacist for proper

disposal.

Keep Sandoz Entecavir and all medicines out of the reach of

children and pets.

General Information:

Medicines are sometimes prescribed for conditions other than

those described in patient information leaflets. Do not use Sandoz

Entecavir for a condition for which it was not prescribed. Do not

give Sandoz Entecavir to other people, even if they have the same

symptoms you have. It may harm them. The leaflet summarizes the

most important information about Sandoz Entecavir. If you would

like more information, talk with your healthcare provider.

Reporting Side Effects

You can report any suspected side effects associated with the

use of health products to Health Canada by:

Visiting the Web page on Adverse Reaction Reporting

(https://www.canada.ca/en/health-

canada/services/drugs-health-products/medeffect-

canada/adversereaction-reporting.html) for

information on how to report online, by mail or by fax;

or

Calling toll-free at 1-866-234-2345.

MORE INFORMATION

If you want more information about Sandoz Gatifloxacin:

Talk to your healthcare professional

Find the full product monograph that is prepared for

healthcare professionals and includes this Patient

Medication Information by visiting the Health Canada

website (https://health-products.canada.ca/dpd-

bdpp/index-eng.jsp ); the manufacturer's website

www.sandoz.com , or by calling 1-800-361-3062.

or by written request at:

110 Rue de Lauzon

Boucherville QC

J4B 1E6

Or by e-mail at :

[email protected]

This leaflet was prepared by Sandoz Canada Inc.

Last revised: October24, 2018

https://health-products.canada.ca/dpd-bdpp/index-eng.jsp

https://health-products.canada.ca/dpd-bdpp/index-eng.jsp

http://www.sandoz.com/

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